Okadaic acid and dinophysistoxin-1, non-TPA-type tumor promoters, stimulate prostaglandin E2 production in rat peritoneal macrophages.

Okadaic acid and dinophysistoxin-1 isolated from a black sponge, Halichondria okadai are non-12-O-tetrade-canoylphorbol 13-acetate (non-TPA)-type tumor promoters of mouse skin. Okadaic acid at concentrations of 10-100 ng/ml stimulated prostaglandin E2 production in rat peritoneal macrophages. Dinophysistoxin-1 (35-methylokadaic acid) stimulated prostaglandin E2 production as strong as okadaic acid, but okadaic acid tetramethyl ether, an inactive compound as a tumor promoter, did not.

The tumor promoters 12-O-tetradecanoylphorbol-13-acetate and okadaic acid differ in toxicity, mitogenic activity and induction of gene expression.

Okadaic acid (OA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) are both potent tumor promoters in a mouse skin carcinogenesis experiment. OA was much more toxic than TPA for murine embryo cell lines such as Swiss 3T3 cells or C3H10T1/2 cells. TPA is a potent mitogen for 3T3 cells; in contrast OA was unable to stimulate DNA synthesis in these cells.

Specific binding of okadaic acid, a new tumor promoter in mouse skin.

The tumor promoter okadaic acid binds specifically to a particulate as well as a cytosolic fraction of various mouse tissues, e.g., skin, brain, lung and colon.

Inhibition of methylnitrosourea-induced large bowel cancer development in rats by sarcophytol A, a product from a marine soft coral Sarcophyton glaucum.

An antitumorigenic effect of sarcophytol A (SaA), a simple monohydroxycembratetraene isolated from a marine soft coral Sarcophyton glaucum, was investigated in rat colon carcinogenesis. Three groups (26 rats each) of female CD-Fischer rats given an intrarectal dose of 2 mg of N-methyl-N-nitrosourea 3 times weekly for Wk 1 to 3 were fed standard laboratory chow in the control group or the chow containing 0.01% SaA from Wk 1 or from Wk 4 in experimental groups.

Inhibitory effect of (-)-epigallocatechin gallate on carcinogenesis with N-ethyl-N'-nitro-N-nitrosoguanidine in mouse duodenum.

(-)-Epigallocatechin gallate (EGCG) is the main polyphenolic constituent of green tea infusion and inhibits tumor promotion by teleocidin in two-stage carcinogenesis on mouse skin. In this work, EGCG was found to inhibit tumor promotion in the gastrointestinal tract in a model system of mouse duodenal carcinogenesis with N-ethyl-N'-nitro-N-nitrosoguanidine. The duodenal tumors that developed were studied stereomicroscopically and histologically.

Stimulation of histamine release and arachidonic acid metabolism in rat peritoneal mast cells by thapsigargin, a non-TPA-type tumor promoter.

Thapsigargin, a non-TPA-type tumor promoter, releases histamine and stimulates arachidonic acid metabolism in rat peritoneal mast cells. In order to clarify the relationship between the histamine-releasing activity and the arachidonic acid metabolism-stimulating activity of thapsigargin in mast cells, the effects of cyclooxygenase inhibitors, indomethacin and ibuprofen, a lipoxygenase inhibitor, AA861, and dual inhibitors for cyclooxygenase and lipoxygenase, nordihydroguaiaretic acid and BW755C, on histamine release and arachidonic acid metabolism were examined. High-performance liquid chromatography analysis revealed that the peritoneal mast cells preferentially produce prostaglandin D2 by thapsigargin treatment.

Apparent "activation" of protein kinases by okadaic acid class tumor promoters.

A cytosolic fraction of mouse brain gave two peaks of protein kinase activity on DEAE-cellulose column chromatography. The first peak of protein kinase corresponded to protein kinase C. The second peak contained protein kinases that were "activated" dose-dependently by the okadaic acid class tumor promoters, okadaic acid and dinophysistoxin-1.

Phosphorylation at threonine-654 is not required for negative regulation of the epidermal growth factor receptor by non-phorbol tumor promoters.

Phosphorylation of the epidermal growth factor (EGF) receptor following activation of protein kinase C appears to negatively regulate EGF binding and the receptor-associated tyrosine kinase activity. We have identified two agents, the calcium ionophore A23187 and the non-phorbol tumor promoter thapsigargin, that similarly inhibit the EGF receptor binding and kinase activities through protein kinase C-independent pathways. Both agents activate protein kinases that phosphorylate the EGF receptor in A431 cells.

Palytoxin down-modulates the epidermal growth factor receptor through a sodium-dependent pathway.

Palytoxin, a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter, has been shown to inhibit epidermal growth factor (EGF) binding to both high and low affinity receptors through a protein kinase C-independent pathway. In the present paper, we have investigated the mechanism of palytoxin action in Swiss 3T3 cells. Two lines of evidence indicate that calcium is not required for palytoxin activity.

Codon 61 mutations in the c-Harvey-ras gene in mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene plus okadaic acid class tumor promoters.

Three okadaic acid class tumor promoters, okadaic acid, dinophysistoxin-1, and calyculin A, have potent tumor-promoting activity in two-stage carcinogenesis experiments on mouse skin. DNA isolated from tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and each of these tumor promoters revealed the same mutation at the second nucleotide of codon 61 (CAA----CTA) in the c-Ha-ras gene, determined by the polymerase chain reaction procedure and DNA sequencing. Three potent 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, TPA, teleocidin, and aplysiatoxin, showed the same effects.

Sarcophytols A and B inhibit tumor promotion by teleocidin in two-stage carcinogenesis in mouse skin.

Sarcophytols A and B, isolated from a soft coral, Sarcophyton glaucum, are cembrane-type diterpenes with different numbers of hydroxyl groups. Sarcophytols A and B inhibited tumor promotion by teleocidin in two-stage carcinogenesis experiments on mouse skin. The inhibitory effect of sarcophytol A was demonstrated with two different initiating doses of 7,12-dimethylbenz[a]anthracene (DMBA): 50 micrograms (experiment 1) and 100 micrograms (experiment 2).

Thapsigargin, a novel promoter, phosphorylates the epidermal growth factor receptor at threonine 669.

Thapsigargin, a protein kinase C-independent tumor promoter, can negatively regulate the epidermal growth factor (EGF) receptor through inhibition of high affinity EGF binding and EGF-stimulated tyrosine kinase activity. In contrast to activators of protein kinase C, thapsigargin does not induce significant phosphorylation of threonine 654. However, thapsigargin does stimulate phosphorylation of the EGF receptor at other serine and threonine residues.

Effects of palytoxin or ouabain on growth and squamous differentiation of human bronchial epithelial cells in vitro.

The effects of the non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter palytoxin on human bronchial epithelial cells was studied in an in vitro serum-free culture system. Unlike the results of previous studies with another tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, palytoxin did not induce squamous differentiation of normal bronchial epithelial cells and was equally cytotoxic for normal human bronchial epithelial cells, a human lung tumor cell line, and human bronchial epithelial cells immortalized by infection with adenovirus 12-SV40 hybrid virus (BEAS-2B cells). Palytoxin did not induce a change in free cytosolic Ca2+ concentration of BEAS-2B cells.

A new tumor promoter from the seed oil of Jatropha curcas L., an intramolecular diester of 12-deoxy-16-hydroxyphorbol.

A new type of phorbol ester, which has a macrocyclic dicarboxylic acid diester structure, was isolated from the seed oil of Jatropha curcas L. (Euphorbiaceae). Based on the results of spectroscopic analyses of the compound and its chemical degradation products, its structure is proposed to be an intramolecular 13,16-diester of 12-deoxy-16-hydroxyphorbol, 12-deoxy-16-hydroxyphorbol-4'-[12',14'-butadienyl]-6'-[16',18',20' - nonatrienyl]-bicyclo[3.

Diarrhetic shellfish toxin, dinophysistoxin-1, is a potent tumor promoter on mouse skin.

Dinophysistoxin-1, 35-methylokadaic acid, is a causative agent of diarrhetic shellfish poisoning. The biological activities and tumor-promoting activity of dinophysistoxin-1 were studied together with those of okadaic acid and 7-O-palmitoyl okadaic acid. Dinophysistoxin-1 is a skin irritant and induces ornithine decarboxylase in mouse skin with the same potency as okadaic acid.

A radioimmunoassay for the teleocidins using 26 (2'-aminoethylthio)-tetrahydroteleocidin A-2 as hapten.

A teleocidin A-2 derivative, 26 (2'-aminoethylthio)-tetrahydroteleocidin A-2, induced ornithine decarboxylase in mouse skin and inhibited the specific binding of [3H]12-O-tetradecanoyl-phorbol-13-acetate to a mouse skin particulate fraction with a potency that was weaker than that of teleocidin A-2 and stronger than that of (-)-indolactam-V. To obtain antibodies, 26 (2'-aminoethylthio)-tetrahydroteleocidin A-2 was covalently linked to bovine albumin with a carbodiimide and the resulting conjugate used for immunization of rabbits. Antibodies directed toward teleocidin were produced as measured by neutralization of teleocidin's capacity to stimulate arachidonic acid metabolism in rat liver cells (the C-9 cell line).

Inhibition by gossypol of tumor promoter-induced arachidonic acid metabolism in rat peritoneal macrophages.

Rat peritoneal macrophages were prelabeled with [3H]arachidonic acid. The release of radioactivity into the medium was increased by treatment with TPA-type tumor promoters, such as TPA, teleocidin and aplysiatoxin, and the non-TPA-type tumor promoter, thapsigargin. Gossypol, at concentrations of 3 and 10 microM, inhibited the release of radioactivity stimulated by both types of tumor promoter, although the mechanism of stimulation of arachidonic acid metabolism is different in the two types of tumor promoter.

Similar, potent tumor-promoting activity of all isomers of teleocidins A and B in a two-stage carcinogenesis experiment on the skin of CD-1 mice.

Teleocidin, isolated from mycelia of Streptomyces mediocidicus is a mixture of two teleocidin A isomers with molecular weights of 437 (A-1 and A-2) and four teleocidin B isomers with molecular weights of 451 (B-1, B-2, B-3, and B-4). Previously we found that each purified isomer of teleocidins A and B had approximately the same activity as teleocidin in an irritant test on mouse ear, in inductions of ornithine decarboxylase in mouse skin and adhesion of human promyelocytic leukemia (HL-60) cells, and in inhibition of the specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to a mouse skin particulate fraction. This paper reports the strong activation of protein kinase C in vitro by each isomer of teleocidins A and B at a concentration of 1 microgram/ml.

Analysis of the stimulative effect of thapsigargin, a non-TPA-type tumour promoter, on arachidonic acid metabolism in rat peritoneal macrophages.

1. At concentrations above 10 ng ml-1, the tumour promoter thapsigargin stimulates the release of radioactivity from [3H]-arachidonic acid-labelled macrophages harvested from rat peritoneal cavity. 2.

Specific binding of [3H]retinoids to cellular retinoid-binding proteins.

The specific binding of [3H]retinoids to cellular retinoid-binding proteins was measured directly by the cold acetone filtration method. After incubation of purified cellular retinoid-binding proteins with [3H]retinoids with or without competitors for 2-4 h, bound ligands were separated from free by filtration using cold acetone. Nonspecific binding of the ligands was reduced sufficiently to allow measurement of specific binding of [3H]retinoids to cellular retinoid-binding proteins.

Hyperphosphorylation of N-60, a protein structurally and immunologically related to nucleolin after tumour-promoter treatment.

Okadaic acid, a non-TPA-type tumour promoter, induces hyperphosphorylation of a 60-kd protein in primary human fibroblasts. Treatment with TPA-type tumour promoters (e.g.

A receptor model for tumor promoters: rational superposition of teleocidins and phorbol esters.

Four 12-O-tetradecanoyl-13-O-acetylphorbol-type tumor promoters--teleocidin, phorbol ester, aplysiatoxin, and ingenol ester--are superposed in an attempt to understand their common biological activity on the assumption that they may bind to the same receptor site. A method using three-dimensional computer graphics was applied for superposing molecules and receptor mapping. The main feature of the method is that molecules are superposed in terms of spatial arrangement of physical and chemical properties but not in terms of the atomic positions as in conventional methods.

Lysis of human immunodeficiency virus infected cells by TPA-type and non-TPA type tumor promoters.

We reported previously that TPA facilitates the replication of human immunodeficiency virus (HIV) and has a selective lethal effect on HIV-infected cells by a cytopathic effect induced by HIV. We have now studied the cytopathic effects of TPA-type tumor promoters (teleocidin, aplysiatoxin, and TPA) and the non-TPA type tumor promoters (palytoxin and thapsigargin) on MOLT-4/HIVHTLV-IIIB cells. All TPA-type and non-TPA type tumor promoters tested except palytoxin stimulated in HIV production three- to sevenfold, and caused more lysis of MOLT-4/HIVHTLV-IIIB cells than of the parental MOLT-4 cells.

Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter.

Okadaic acid is a polyether compound of a C38 fatty acid, isolated from a black sponge, Halichondria okadai. Previous studies showed that okadaic acid is a skin irritant and induces ornithine decarboxylase (OrnDCase; 3-hydroxyl-L-glutamate 1-carboxy-lyase, EC 4.1.